Method of Treating Cancer and Other Conditions or Disease States Using L-Cytosine Nucleoside Analogs

ABSTRACT

The present invention relates to the use of the compound according to formula (I) Where S is (A) or (B); X is H or F; R 1  is H, an acyl group, a C 1 -C 20  alkyl or ether group, a phosphate, diphosphate, triphosphate or a phosphodiester group, a (C) or (D) group; Where Nu is a radical of a biologically active compound such as an anticancer, antihyperproliferative or antiviral compound such that an amino group or hydroxyl group from said biologically active agent forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety; Each R 8  is independently H, or a C 1 -C 20  alkyl or ether group, preferably H or a C 1 -C 2  alkyl group; k is 0-12, preferably, 0-2; R 2  is H, an acyl group or a C 1 -C 20  alkyl or ether group; and pharmaceutically acceptable salts, solvates or polymorphs thereof for the treatment of tumors, cancer and hyperproliferative diseases, among other conditions or disease states.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional applicationUS60/741,730, filed Dec. 2, 2005, the entire contents of which isincorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to the use of lamivudine (3TC), emtricitabine(FTC), and Elvucitabine (L-FD4C or LFD4C), prodrugs or conjugatescomprising these agents alone or along with another active agent,especially an anticancer agent or prodrug in the treatment of tumors,including cancer, and hyperproliferative diseases, chronic inflammatorydiseases and certain viral and other microbial infections alone or incombination with another agent.

BACKGROUND OF THE INVENTION

A tumor is an unregulated, disorganized proliferation of cell growth. Atumor is malignant, or cancerous, if it has the properties ofinvasiveness and metastasis. Invasiveness refers to the tendency of atumor to enter surrounding tissue, breaking through the basal laminasthat define the boundaries of the tissues, thereby often entering thebody's circulatory system. Metastasis refers to the tendency of a tumorto migrate to other areas of the body and establish areas ofproliferation away from the site of initial appearance.

Cancer is now the second leading cause of death in the United States.Over 8,000,000 persons in the United States have been diagnosed withcancer, with 1,208,000 new diagnoses expected in 1994. Over 500,000people die annually from the disease in this country.

Cancer is not fully understood on the molecular level. It is known thatexposure of a cell to a carcinogen such as certain viruses, certainchemicals, or radiation, leads to DNA alteration that inactivates a“suppressive” gene or activates an “oncogene”. Suppressive genes aregrowth regulatory genes, which upon mutation, can no longer control cellgrowth. Oncogenes are initially normal genes (called prooncogenes) thatby mutation or altered context of expression become transforming genes.The products of transforming genes cause inappropriate cell growth. Morethan twenty different normal cellular genes can become oncogenes bygenetic alteration Transformed cells differ from normal cells in manyways, including cell morphology, cell-to-cell interactions, membranecontent, cytoskeletal structure, protein secretion, gene expression andmortality (transformed cells can grow indefinitely).

All of the various cell types of the body can be transformed into benignor malignant tumor cells. The most frequent tumor site is lung, followedby colorectal, breast, prostate, bladder, pancreas, and then ovary.Other prevalent types of cancer include leukemia, central nervous systemcancers, including brain cancer, melanoma, lymphoma, erythroleukemia,uterine cancer, and head and neck cancer.

Cancer is now primarily treated with one or a combination of three typesof therapies: surgery, radiation, and chemotherapy. Surgery involves thebulk removal of diseased tissue. While surgery is sometimes effective inremoving tumors located at certain sites, for example, in the breast,colon, and skin, it cannot be used in the treatment of tumors located inother areas, such as the backbone, nor in the treatment of disseminatedneoplastic conditions such as leukemia.

Chemotherapy involves the disruption of cell replication or cellmetabolism. It is used most often in the treatment of leukemia, as wellas breast, lung, and testicular cancer.

There are five major classes of chemotherapeutic agents in use for thetreatment of cancer: natural products and their derivatives;anthracyclines; alkylating agents; antiproliferatives (also calledantimetabolites); and hormonal agents. Chemotherapeutic agents are oftenreferred to as antineoplastic agents.

The alkylating agents are believed to act by alkylating andcross-linking guanine and possibly other bases in DNA, arresting celldivision. Typical alkylating agents include nitrogen mustards,ethyleneimine compounds, alkyl sulfates, cisplatin, and variousnitrosoureas. A disadvantage with these compounds is that they not onlyattack malignant cells, but also other cells which are naturallydividing, such as those of bone marrow, skin, gastro-intestinal mucosa,and fetal tissue.

Antimetabolites are typically reversible or irreversible enzymeinhibitors, or compounds that otherwise interfere with the replication,translation or transcription of nucleic acids.

Several synthetic nucleosides have been identified that exhibitanticancer activity. A well known nucleoside derivative with stronganticancer activity is 5-fluorouracil. 5-Fluorouracil has been usedclinically in the treatment of malignant tumors, including, for example,carcinomas, sarcomas, skin cancer, cancer of the digestive organs, andbreast cancer. 5-Fluorouracil, however, causes serious adverse reactionssuch as nausea, alopecia, diarrhea, stomatitis, leukocyticthrombocytopenia, anorexia, pigmentation, and edema. Derivatives of5-fluorouracil with anti-cancer activity have been described in U.S.Pat. No. 4,336,381, and in Japanese patent publication Nos. 50-50383,50-50384, 50-64281, 51-146482, and 53-84981.

U.S. Pat. No. 4,000,137 discloses that the peroxidate oxidation productof inosine, adenosine, or cytidine with methanol or ethanol has activityagainst lymphocytic leukemia.

Cytosine arabinoside (also referred to as Cytarabin, araC, and Cytosar)is a nucleoside analog of deoxycytidine that was first synthesized in1950 and introduced into clinical medicine in 1963. It is currently animportant drug in the treatment of acute myeloid leukemia. It is alsoactive against acute lymphocytic leukemia, and to a lesser extent, isuseful in chronic myelocytic leukemia and non-Hodgkin's lymphoma. Theprimary action of araC is inhibition of nuclear DNA synthesis.Handschumacher, R. and Cheng, Y., “Purine and PyrimidineAntimetabolites”, Cancer Medicine, Chapter XV-1, 3rd Edition, Edited byJ. Holland, et al., Lea and Febigol, publishers.

5-Azacytidine is a cytidine analog that is primarily used in thetreatment of acute myelocytic leukemia and myelodysplastic syndrome.

2-Fluoroadenosine-5′-phosphate (Fludara, also referred to as FaraA)) isone of the most active agents in the treatment of chronic lymphocyticleukemia. The compound acts by inhibiting DNA synthesis. Treatment ofcells with F-araA is associated with the accumulation of cells at theG1/S phase boundary and in S phase; thus, it is a cell cycle Sphase-specific drug. Incorporation of the active metabolite, F-araATP,retards DNA chain elongation. F-araA is also a potent inhibitor ofribonucleotide reductase, the key enzyme responsible for the formationof dATP.

2-Chlorodeoxyadenosine is useful in the treatment of low grade B-cellneoplasms such as chronic lymphocytic leukemia, non-Hodgkins' lymphoma,and hairy-cell leukemia. The spectrum of activity is similar to that ofFludara. The compound inhibits DNA synthesis in growing cells andinhibits DNA repair in resting cells.

Although a number of chemotherapeutic agents have been identified andare currently used for the treatment of cancer, new agents are soughtthat are efficacious and which exhibit low toxicity toward healthycells.

U.S. Pat. Nos. 5,817,667 and 6,063,787 disclose the use of β-LOddC forthe treatment of tumors, including cancer or for the treatment ofpsoriasis and related hyperproliferative diseases/conditions.

OBJECTS OF THE INVENTION

Therefore, it is an object of the present invention to provide compoundsand pharmaceutical compositions that exhibit anti-tumor, and inparticular, anti-cancer and/or anti-hyperproliferative growth diseaseactivity.

It is another object of the present invention to provide pharmaceuticalcompositions for the treatment of cancer and hyperproliferative cellgrowth diseases.

It is further object of the present invention to provide a method forthe treatment of cancer and hyperproliferative cell growth diseases.

Any one or more of these and/or other objects of the invention may bereadily gleaned from a review of the description of the invention whichfollows.

SUMMARY OF THE INVENTION

The present invention relates to the use of the compound according toformula I, below for the treatment of tumors, cancer andhyperproliferative diseases:

Where S is

X is H or F;

R¹ is H, an acyl group, a C₁-C₂₀ alkyl or ether group, a phosphate,diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as ananticancer or antiviral compound such that an amino group or hydroxylgroup from said biologically active agent forms a phosphate,phosphoramidate, carbonate or urethane group with the adjacent moiety;Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferablyH or a C₁-C₁₂ alkyl group;k is 0-12, preferably, 0-2;R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group;and pharmaceutically acceptable salts, solvates or polymorphs thereof.In preferred aspects of the present invention, R¹ is H, a C₂-C₁₈ acylgroup or a phosphate group and R² is H.

Pharmaceutical compositions comprising an anti-cancer effective amountof one or more of the compounds of formula 1, optionally (andpreferably) in combination with an effective amount of at least oneadditional anti-cancer agent as otherwise described herein and at leastone carrier, additive or excipient are additional aspects of the presentinvention.

Further aspects of the present invention relate to methods for treatinghyperproliferative diseases, including tumors, especially malignanttumors and cancer. This aspect(s} of the present invention is directedto methods of treating tumors, cancer, hyperproliferative diseases,including psoriasis, genital warts (papilloma), hyperproliferative cellgrowth such as abnormal cell proliferation or growth of non-transformedcells including precancerous cells, and any cell which expresses anabnormal or foreign cell surface protein or antigen. Methods fortreating chronic inflammatory diseases and viral and other microbialinfections alone or in combination with another agent are furtheraspects of the invention.

The method aspect includes treating hyperproliferative diseasesincluding psoriasis, genital warts and hyperproliferative cell growthdiseases, including hyperproliferative keratinocyte diseases such ashyperkeratosis, ichthyosis, keratoderma or lichen planus and chronicinflammatory diseases such as arthritis, including rheumatoid arthritisand osteoarthritis as well as hepatitis C virus (HCV) infections, themethods comprising administering to a patient in need thereof aneffective amount of a compound according to the present invention,optionally in combination with at least one additional anti-canceragent, optionally in combination with a pharmaceutically acceptablecarrier, additive or excipient.

Virtually any cancer can be treated using the compositions and methodsaccording to the present invention. Exemplary cancers which may treatedinclude, for example, stomach, colon, rectal, liver, pancreatic, lung,breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder,renal, brain/CNS, head and neck, throat, Hodgkin's disease,non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, acutelymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, smallcell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor,neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx,kidney cancer and lymphoma, among numerous others.

It is noted that the use of 3TC, FTC or LFD4C or their derivatives inthe treatment of cancer exhibits little, if any, anticancer activity,and when coadministered with another anti-cancer agent in the treatmentof cancer in a subject, is substantially more active than the otheranti-cancer agent alone, which is an unexpected result. Moreover, acombination of an effective amount of one of the nucleoside compoundsaccording to the present invention with another anticancer agent (“theother anticancer agent”), in many instances, will provide a synergisticenhancement (i.e., more than additive) of the anticancer activity of theother anticancer agent. The enhancement of the host defense againstabnormal tissue such as cancer is the likely explanation. Thus, thepresent compounds could also be useful for the treatment of otherdisease tissues such as viral infected cells, among others, even thoughthe compounds may not exhibit direct activity against the microorganismsinfecting those tissues.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1-2 show the effects of 3TC, FTC or LFD4C either alone or incombination with other anti-cancer agents on tumors/cancer as indicatedin the figures and the experimental section.

DETAILED DESCRIPTION OF THE INVENTION

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein. Within its use incontext, the term generally refers to a single compound preferably, L-βanomers of nucleoside analogs (3TC, FTC or LFD4C) or its variousracemic, enantiomerically enriched (to at least 75%, 85%, 95%, 98%, 99%or 99+% enantiomeric enrichment) or various prodrug or derivative formsas otherwise described herein. B-L nucleoside compounds according toformula I which are used in the present invention are referred togenerally as 3TC, FTC or LFD4C or its derivatives. Compounds accordingto the present invention exhibit little, if any toxicity, to host cellsin treating cancer, an unexpected result.

The term “effective” is used herein, unless otherwise indicated, todescribe an amount of a compound which, in context, is used to produceor effect an intended result, whether that result relates to thetreatment of a hyperproliferative disease state, chronic inflammatorydisease, a viral infection such as a HCV infection, a tumor including acarcinogenic tumor or other cancer or the treatment of a precancerouslesion or other cell(s) which express abnormal or foreign proteins orimmunogens on a cell surface. In certain aspects the present inventionrelates to the enhancement of the anti-cancer effect of anotheranti-cancer compound. This term subsumes all other effective amount oreffective concentration terms which are otherwise described in thepresent application. With respect to an anticancer effect, that effectmay be one or more of inhibiting further growth of tumor or cancercells, reducing the likelihood or eliminating metastasis or producingcell death in the tumor or cancer cells, resulting in a shrinkage of thetumor or a reduction in the number of cancer cells or preventing theregrowth of a tumor or cancer after the patient's tumor or cancer is inremission. As indicated, 3TC, FTC or LFD4C or its derivatives mayexhibit an anti-cancer effect alone and/or may enhance the ability ofanother anticancer agent to exhibit an anti-cancer effect.

The term “patient” or “subject” is used throughout the specification todescribe an animal, generally a mammal and preferably a human, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present invention is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe a salt form of one or more of the compositions(and in particularly preferred aspects according to the presentinvention, phosphate salts) herein which are presented to increase thesolubility of the compound in saline for parenteral delivery or in thegastric juices of the patient's gastrointestinal tract in order topromote dissolution and the bioavailability of the compounds.Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic or organic bases and acids.Suitable salts include those derived from alkali metals such aspotassium and sodium, alkaline earth metals such as calcium, magnesiumand ammonium salts, among numerous other acids well known in thepharmaceutical art. Sodium and potassium salts are particularlypreferred as neutralization salts of carboxylic acids and free acidphosphate containing compositions according to the present invention.The term “salt” shall mean any salt consistent with the use of thecompounds according to the present invention. In the case where thecompounds are used in pharmaceutical indications, including thetreatment of neoplasia, including cancer, the term “salt” shall mean apharmaceutically acceptable salt, consistent with the use of thecompounds as pharmaceutical agents.

The term “pharmaceutically acceptable derivative” or “derivative” isused throughout the specification to describe any pharmaceuticallyacceptable prodrug form (such as an ester or ether or other prodruggroup) which, upon administration to a patient, provides directly orindirectly the present compound or an active metabolite of the presentcompound.

The term “alkyl” shall mean within its context a C₁-C₂₀, preferably aC₁-C₁₀ linear, branch-chained or cyclic fully saturated hydrocarbonradical, which may be optionally substituted, such as with a phenylgroup, for example. The term “ether” shall mean a C₁ to C₂₀ ether group,formed from an oxygen and an alkyl group at a position on the sugarmoiety of compounds according to the present invention, and preferablycontains at least one oxygen group within the alkyl chain. The termalkyl shall also embrace aralkyl groups such as benzyl groups, whichphenyl group may be optionally substituted.

The term “acyl” is used throughout the specification to describe a groupat the 5′ position of the nucleoside analog (i.e., at the free hydroxylposition in the sugar synthon) which contains a C₁ to C₂₀ linear,branched or cyclic alkyl chain or a related group as otherwise describedherein. The acyl group at the 5′ position (R¹), in combination with thecorresponding hydroxyl group results in an ester, which, afteradministration, may be cleaved to produce the free nucleoside form ofthe present invention. Acyl groups according to the present inventionmay be represented by the structure:

where R₄ is a C₁ to C₂₀ linear, branched or cyclic alkyl group,alkoxyalkyl, aryloxyalkyl, such as phenoxymethyl, aryl, alkoxy, all ofwhich may be optionally substituted, among others. Preferred acyl groupsare those where R₄ is a C₁ to C₁₀ alkyl group. Acyl groups according tothe present invention also include, for example, those acyl groupsderived from benzoic acid and related acids, 3-chlorobenzoic acid,succinic, capric and caproic, lauric, myristic, palmitic, stearic andoleic groups, amino acids, among numerous others including certainpharmaceutically acceptable sulphonate groups, which are also consideredacyl groups for purposes herein. One of ordinary skill in the art willrecognize the acyl groups which will have utility in the presentinvention, either to synthesize the target pharmaceutical compounds oras prodrug forms of the nucleosides according to the present invention.

The term “phosphate ester” or “phosphodiester” is used throughout thespecification to describe mono-phosphate groups at the 5′ position ofthe sugar synthon which are diesterified such that the phosphate groupis rendered neutral, i.e., has a neutral charge. Phosphate esters foruse in the present invention include those represented by thestructures:

where R₅, R₆ and R″ are selected from a C₁ to C₂₀ linear, branched orcyclic alkyl group, alkoxyalkyl, aryloxyalkyl, such as phenoxymethyl,aryl and alkoxy, among others, and R₇ is a C₁ to C₂₀ linear, branched orcyclic alkyl or acyl group, alkoxyalkyl, aryloxyalkyl, such asphenoxymethyl, aryl and alkoxy, among others. Preferred monophosphateesters for use in prodrug forms according to the present invention arethose where R₅ is a C₁ to C₂₀ linear or branched chain alkyl group, morepreferably a C₁ to C₃ alkyl group.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Representative cancers include, for example, stomach,colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpusuteri ovary, prostate, testis, bladder, renal, brain/CNS, head and neck,throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma,leukemia, melanoma, acute lymphocytic leukemia, acute myelogenousleukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma,rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia,mouth/pharynx, oesophagus, larynx, kidney cancer and lymphoma, amongothers, which may be treated by one or more compounds according to thepresent invention.

The term “tumor” is used to describe a malignant or benign growth ortumefacent.

The term “hyperproliferative disease state” refers to a disease state inwhich cells are growing in an uncontrolled manner, whether that growthis cancerous or not. Such a disease state may be reflected in psoriasis,genital warts or other hyperproliferative cell growth diseases,including hyperproliferative keratinocyte diseases includinghyperkeratosis, ichthyosis, keratoderma or lichen planus, all of whichdisease states may be treated using compounds according to the presentinvention.

The term “anti-cancer compound” or “anti-cancer agent” is used todescribe any compound (including its derivatives) which may be used totreat cancer. Anticancer compounds for use in the present invention maybe co-administered with one or more of 3TC, FTC, or LFD4 or theirderivatives for the effect that each of these compounds or theirderivative compounds have on enhancing the effect of the anti-cancercompound in treating cancer in a patient pursuant to the presentinvention. In many instances the co-administration of these compounds ortheir derivative and another anti-cancer compound results in asynergistic anti-cancer effect. Exemplary anti-cancer compounds for usein the present invention for co-administration with 3TC, FTC, or LFD4 ortheir derivative include anti-metabolites agents which are broadlycharacterized as antimetabolites, inhibitors of topoisomerase I and II,alkylating agents and microtubule inhibitors (e.g., taxol). Anti-cancercompounds for use in the present invention include, for example,Aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine;amifostine; anastrozole; arsenic trioxide; Asparaginase; BCG Live;bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous;busulfan oral; calusterone; capecitabine; carboplatin; carmustine;carmustine with Polifeprosan 20 Implant; celecoxib; chlorambucil;cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabineliposomal; dacarbazine; dactinomycin; actinomycin D; Darbepoetin alfa;daunorubicin liposomal; daunorubicin, daunomycin; Denileukin diftitox,dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal;Dromostanolone propionate; Elliott's B Solution; epirubicin; Epoetinalfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane;Filgrastim; floxuridine (intraarterial); fludarabine; fluorouracil(5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate;hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinibmesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole;leucovorin; levamisole; lomustine (CCNU); mechlorethamine (nitrogenmustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP);mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone;nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin;paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim;pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium;procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim;streptozocin; talbuvidine (LDT); talc; tamoxifen; temozolomide;teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa;topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA);Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine;vinorelbine; zoledronate; and mixtures thereof, among others.

The term “bioactive agent” includes any biologically active agent,including a prodrug form of the active agent, which can be administeredin combination with 3TC, FTC or LFD4C or a derivative (such as a prodrugform) pursuant to the present invention and can include active agents ortheir derivatives which form dual acting agents wherein the bioactiveagent or its derivative and the nucleoside compounds or its derivative(referred to collectively as conjugates) are chemically linked asotherwise described herein. In addition to anti-cancer agents asotherwise described above, bioactive agents may include a number ofantiviral agents including for example, the following agents, which areuseful for the treatment of HIV, HBV and other viral infections as wellas agents which treat hyperproliferative diseases and chronicinflammatory diseases such as arthritis, including rheumatoid arthritisand osteoarthritis, among number others.

In addition to the anticancer agents described above, exemplarybioactive agents which may be chemically linked to 3TC, FTC, LFD4C or aderivative as described herein include for example,

-   -   Atazanavir (BMS-232632) using the free secondary hydroxyl group;    -   Bis(POM)-PMEA (Adefovir dipivoxyl) using the free amine group;    -   Bis(POC)-PMPA (Tenofovir disoproxil) using the free amine group;    -   Etecavir using the primary hydroxyl group on the carbocyclic        sugar synthon;    -   Indinavir (Crixivan, MK-639 L-735,524 from Merck) using the free        secondary hydroxyl group;    -   KHI-227 (Kynostatin of Nikko Kyodo Co.) using the free secondary        hydroxyl group:    -   2-[3-[3-(S)-[[(Tetrahydrofuranyloxy)carbonyl]amino]phenyl-2(R)-hydroxybutyl]]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide        (IsoquinCON furanyl urethane analog from Merck) using the free        secondary hydroxyl group;    -   Carbamic acid,        [3-{[(4-methoxyphenyl)sulfonyl](cyclopenylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-,        tetrahydrofuranyl ester (VB-11,328 of Vertex) using the free        secondary hydroxyl group;    -   KNI-174 from Nikko Kyodo Co. using the free secondary hydroxyl        (or free amine) group;    -   Val-Val-Sta from Sandoz (Austria) using the free secondary        hydroxyl group;    -   CPG53820 from Ciba-Geigy using the free secondary hydroxyl        group;    -   bis-Val HOEt-N2 aza-peptide isostere using the free secondary        hydroxyl group;    -   C2-Sym Phosphinic amide derivative from Hoechst AG using the        free amine group;    -   2,5,-Diamino-N,N′-bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(S),        4(S)hexanediol BzOCValPhe[diCHOH(SS]PheValBzOC from Abbott using        the free secondary hydroxyl group;    -   2,5,-Diamino-N,N′-bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(R),        4(R)-hexanediol BzOCValPhe[diCHOH(RR]PheValBzOC from Abbott        using the free secondary hydroxyl group;    -   bis(S-acetyl-2-thioethyl)phosphotriester of ddA        or[bis(SATE)ddAMP] using the free amine;    -   BILA 2186 BS(Bio-Mega/Boehringer Ingelheim) using the free        secondary hydroxyl group;    -   Agenerase (Amprenavir; VX-478; 141W94) of Vertex/Kissei/Glaxo        Wellcome at the free secondary hydroxyl or amine group;    -   A-98881 (Azacyclic urea derivative) of Abbott using the free        secondary hydroxyl group or phenolic hydroxyl group;    -   A-83962 (Rifonavir derivative) of Abbott using the free        secondary hydroxyl group;    -   A-80987 (Rifonavir derivative) of Abbott using the free        secondary hydroxyl group;    -   (2-Naphthalcarbonyl)Asn[decarbonylPhe-hydroxyethyl]ProOtertButyl        or 2-NaphCOAsnPhe[CHOHCH2]Pro-OtBu of Roche using the free        secondary hydroxyl;    -   2-Aminobenzylstatine Valyl Cbz derivative of Sandoz using the        free secondary hydroxyl or amine;    -   2-Aminobenzylstatine Valyl Cbz derivative of Sandoz using the        free hydroxyl;    -   10H-2(CbzValNH)3PhPr[14]paracyclophane derivative of Sandoz        using the free secondary hydroxyl;    -   10H-2(Cbz-ValNH)3PhPr[1,3]paracyclophane derivative of Sandoz        using the free secondary hydroxyl;    -   10H-2(Cbz-ValNH)3PhPr[13]metacyclophane derivative of Sandoz        using the free secondary hydroxyl;    -   10H-2(Cbz-Tle)3PhPr[14]paracyclophane derivative of Sandoz using        the free secondary hydroxyl;    -   1-(20HPr)-4-substituted-piperazine (cyclopropyl), thieneyl        carbamate deriv. (from Merck) using the free secondary hydroxyl        group;    -   1-(20HPr)-4-substituted-piperazine (cyclobutyl), thienyl        carbamate derive. (from Merck) using the free secondary hydroxyl        group;    -   1-(20HPr)-4-substituted-piperazine (3-pentyl), thienyl carbamate        derive. (from Merck) using the free secondary hydroxyl group;    -   10H-2(Cbz-ValNH3PhPr[17]paracyclophane derivative (from Sandoz)        using the free second hydroxyl group;    -   A-81525 (from Abbott) using the free secondary hydroxyl group;    -   XM323 (DMP-323 from DuPont Merck) using the free primary or        secondary hydroxyl groups;    -   Tipranavir (U-140690 or PHU-140690 from Pharmacia & Upjohn)        using the phenolic hydroxyl group;    -   ThienopyridCON thienyl urethane derivatives (HOCH2CH2 isostere        from Lilly) (the benzyl substituted derivative or the methyl        mercaptophenyl substituted derivatives) using the free secondary        hydroxyl groups;    -   SDZ PRI053 (Sandoz) using the free secondary hydroxyl group;    -   SD 146 (DuPont Merck) using either of the free secondary        hydroxyl groups;    -   Telinavir (SC-52151 from Searle/Monsanto) using the free        secondary hydroxyl group or amine;    -   (R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu (from Roche) using the free        secondary hydroxyl group or amine;    -   Saquinavir (Invirase or RO 31-8959 from Roche) using the free        secondary hydroxyl group or amine;    -   Saquinavir/Melfinavir derivative (from Lilly) using the free        secondary hydroxyl group;    -   IsoquinCON Thf-Thf Urethane Analog (from Merck) using the free        secondary hydroxyl group;    -   IsoquinCON thienyl urethane analog (from Merck) using the free        secondary hydroxyl group;    -   R-87366 (AHPBA analog from Sankyo) using the free amine group;    -   DMP 460 (Dupont Merck/Avid) using the free secondary hydroxyl        groups or either of the aniline amine groups;    -   L685,434 (Merck) using the free secondary hydroxyl group;    -   L685, 434-6-Hydroxyl derivative (Merck) using the free secondary        hydroxyl group;    -   L685,434-OEtNMe2 (Merck) using the free secondary hydroxyl        group;    -   L685,434-OPrMorph derivative (Merck) using the free secondary        hydroxyl group;    -   L689,502 (Merck) using the free secondary hydroxyl group;    -   Lasinavir (CGP 61755 from CIBA/Novartis) using the free        secondary hydroxyl group;    -   Aluviran (Lopinavir, ABT-378, RS-346 A157378 of Abbott) using        the free secondary hydroxyl group;    -   Nelfinavir-octahydro-thienopyridine analog (from Lilly) using        the free secondary hydroxyl group;    -   P9941 (from DuPot Merck) using either of the free secondary        hydroxyl groups;    -   Palinavir (BILA 2011 BS from BIO-MEGA/Boehringer Ingelheim)        using the free secondary hydroxyl group;    -   Penicillin, 2Isoquin-OHPrNH2 analog (from Glaxo Wellcome) using        the free secondary hydroxyl group, among numerous others.

The above active compounds, and other relevant bioactive agents for usein the dual antagonist aspect of the present invention may be found atthe NIH website at www.niaid.nih.gov/daids/dtpdb/, relevant portions ofwhich are incorporated by reference herein.

The term “coadministration” or “combination therapy” is used to describea therapy in which at least two active compounds in effective amountsare used to treat cancer or another disease state or condition asdescribed herein at the same time. The result may be additive orpreferably and in most instances, synergistic. Although the termcoadministration preferably includes the administration of two activecompounds to the patient at the same time, it is not necessary that thecompounds be administered to the patient at the same time, althougheffective amounts of the individual compounds will be present in thepatient at the same time. Compounds according to the present inventionare preferably administered with one or more anti-cancer agent,including antimetabolites, alkylating agents, topoisomerase I andtopoisomerase II inhibitors as well as microtubule inhibitors.Anti-cancer compounds for use in the present invention include, forexample, Aldesleukin; Alemtuzumab; alitretinoin; allopurinol;altretamine; amifostine; anastrozole; arsenic trioxide; Asparaginase;BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfanintravenous; busulfan oral; calusterone; capecitabine; carboplatin;carmustine; carmustine with Polifeprosan 20 Implant; celecoxib;chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine;cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D;Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin;Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicinliposomal; Dromostanolone propionate; Elliott's B Solution; epirubicin;Epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16);exemestane; Filgrastim; floxuridine (intraarterial); fludarabine;fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelinacetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide;imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan;letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine(nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine(6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane;mitoxantrone; nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin;oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase;Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin;porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab;Sargramostim; streptozocin; talbuvidine (LDT); talc; tamoxifen;temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG);thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin(ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC);vinblastine; vinorelbine; zoledronate; and mixtures thereof, amongothers.

The present invention includes the compositions comprising thepharmaceutically acceptable salts of compounds of the present invention.The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the aforementioned compounds useful in this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3 naphthoate)]salts, among others.

The invention also includes compositions comprising base addition saltsof the present compounds. The chemical bases that may be used asreagents to prepare pharmaceutically acceptable base salts of thepresent compounds that are acidic in nature are those that formnon-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (eg.,potassium and sodium) and alkaline earth metal cations (e, calcium andmagnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines, among others.

The compounds of this invention primarily related to nucleosidecompounds which are characterized as β-L nucleosides, but can includeother stereoisomers where relevant, including optical isomers of thepresent compounds, as well as racemic, diastereomeric and other mixturesof such isomers, as well as all solvates and polymorphs of thecompounds.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers and may also be administered in controlled-releaseformulations. Pharmaceutically acceptable carriers that may be used inthese pharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially to treat skin cancers, psoriasis orother diseases which occur in or on the skin. Suitable topicalformulations are readily prepared for each of these areas or organs.Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-acceptable transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of compound in a pharmaceutical composition of the instantinvention that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. Preferably, thecompositions should be formulated to contain between about 0.5 milligramto about 750 milligrams, more preferably about 1 milligram to about 600milligrams, and even more preferably about 10 milligrams to about 500milligrams of active ingredient.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

Other aspects of the present invention are directed to methods oftreating tumors, cancer, precancerous cells and lesions, cells whichexpress abnormal or foreign surface proteins or antigens, psoriasis,genital warts (papilloma), chronic inflammatory diseases such asarthritis, rheumatoic arthritis and osteoarthritis, hyperproliferativecell growth diseases, including hyperproliferative keratinocyte diseasessuch as hyperkeratosis, ichthyosis, keratoderma or lichen planus and HCVthe method comprising administering to a patient in need of treatmentthereof an effective amount of a compound according to the formula:

Where S is

X is H or F;

R¹ is H, an acyl group, a C₁-C₂₀ alkyl or ether group, a phosphate,diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as ananticancer or antiviral compound such that an amino group or hydroxylgroup from said biologically active agent forms a phosphate,phosphoramidate, carbonate or urethane group with the adjacent moiety;Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferablyH or a C₁-C₁₂ alkyl group;k is 0-12, preferably, 0-2;R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group;and pharmaceutically acceptable salts, solvates or polymorphs thereof.In preferred aspects of the present invention, R¹ is H, a C₂-C₁₈ acylgroup or a phosphate group and R² is H.In preferred aspects of the present invention, the above compound isco-administered with at least one additional anti-cancer agent or agentwhich is effective against hyperproliferative cell growth diseases. Inother preferred aspects of the present invention, R¹ is H, a C₂-C₁₈ acylgroup or a phosphate group and R² is H. In still other preferredaspects, the compounds used in the methods according to the presentinvention are:

Where X is F or H.

Specific examples of pharmaceutically acceptable derivatives of 3TC, FTCor LFD4C include, but are not limited to: compounds wherein R¹ isselected from the group consisting of alkyl and acyl, specificallyincluding but not limited to methyl, ethyl, propyl, butyl, pentyl,hexyl, isopropyl, isobutyl, sec-butyl t-butyl, isopentyl, amyl t-pentyl,3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl,cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, propionyl, butyryl,valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic,oleic, and amino acids including but not limited to alanyl valinyl,leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl,methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl,asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, andhistidinyl, and wherein R² is H.

3TC, FTC or LFD4C or their derivative can be provided in the form ofpharmaceutically acceptable salts. As used herein, the termpharmaceutically acceptable salts or complexes refers to salts orcomplexes (solvates, polymorphs) of 3TC, FTC or LFD4C that retain thedesired biological activity of the parent compound and exhibit minimal,if any, undesired toxicological effects. Nonlimiting examples of suchsalts are (a) acid addition salts formed with inorganic acids (forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, nitric acid, and the like), and salts formed with organic acidssuch as acetic acid, oxalic acid, tartaric acid, succinic acid, malicacid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginicacid, polyglutamic acid, naphthalenesulfonic acids,naphthalenedisulfonic acids, and polygalacturonic acid; (b) baseaddition salts formed with polyvalent metal cations such as zinc,calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel,cadmium, sodium, potassium, and the like, or with an organic cationformed from N,N-dibenzylethylene-diamine, ammonium, or ethylenediamine;or (c) combinations of (a) and (b); e.g., a zinc tannate salt or thelike.

Modifications of the active compound, specifically at the 5′-O and N-4positions, can affect the solubility, bioavailability and rate ofmetabolism of the active species, thus providing control over thedelivery of the active species. Further, the modifications can affectthe anticancer activity of the compound, in some cases increasing theactivity over the parent compound. This can easily be assessed bypreparing the derivative and testing its anticancer activity accordingto the methods described herein, or other method known to those skilledin the art.

Preparation and Administration of the Active Compounds and Compositions

3TC, FTC or LFD4C or their derivatives can be prepared according to themethods disclosed in detail in the art or by any other method known tothose skilled in the art. In the case of compounds which contain twoactive agents, linking of 3TC, FTC, LFD4C or its derivatives to anotheractive agent may be readily accomplished following standard techniques.Appropriate blocking groups and agents to form the linking groups may beused readily.

Humans, equines, canines, bovines and other animals, and in particular,mammals, suffering from cancer can be treated by administering to thepatient (subject) an effective amount of 3TC, FTC, LFD4C or theirderivatives, including pharmaceutically acceptable salts, solvates orpolymorphs, thereof optionally in a pharmaceutically acceptable carrieror diluent, either alone, or in combination with other known anticanceror pharmaceutical agents. This treatment can also be administered inconjunction with other conventional cancer therapies, such as radiationtreatment or surgery.

These compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid, cream, gel, or solid form, orby aerosol form.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. A preferred doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kgper day, more generally 0.5 to about 25 mg per kilogram body weight ofthe recipient/patient per day. A typical topical dosage will range from0.01-3% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-250 mg is often convenient.

The active ingredient is preferably administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, preferablyabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound or its prodrug derivative can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active compound or pharmaceutically acceptable salts thereof canalso be mixed with other active materials that do not impair the desiredaction, or with materials that supplement the desired action, such asother anticancer agents, antibiotics, antifungals, antiinflammatories,or antiviral compounds. In preferred aspects of the invention, 3TC, FTCor LFD4C or their derivative are coadministered with another anticanceragent, as otherwise described herein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers.These may be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811 (which isincorporated herein by reference in its entirety). For example, liposomeformulations may be prepared by dissolving appropriate lipid(s) (such asstearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline,arachadoyl phosphatidyl choline, and cholesterol) in an inorganicsolvent that is then evaporated, leaving behind a thin film of driedlipid on the surface of the container. An aqueous solution of the activecompound are then introduced into the container. The container is thenswirled by hand to free lipid material from the sides of the containerand to disperse lipid aggregates, thereby forming the liposomalsuspension.

Biological Activity

A wide variety of biological assays have been used and are accepted bythose skilled in the art to assess anti-cancer activity of compounds.Any of these methods can be used to evaluate the activity of thecompounds disclosed herein.

One common method of assessing activity is through the use of theNational Cancer Institute's (“NCI”) test panels of cancer cell lines.These tests evaluate the in vitro anti-cancer activity of particularcompounds, and provide predictive data with respect to the use of testedcompounds in vivo. Other assays include in vivo evaluations of thecompound's effect on human or mouse tumor cells implanted into orgrafted onto nude mice.

EXAMPLES

In these examples, the subject of the present invention, 3TC, FTC orLFD4C are used to determine the effect on tumor growth in a number ofstrains of mice.

In general, the following protocol was used to implant mice with tumorcell lines and to test drugs for the anti-cancer effect.

Passage of Colon 38:

This tumor is passed from a solid tumor growing in mice. Several grams(assuming a gram per ml) are pressed through a sterile screen andsuspended in a tissue culture media without phenol red or fetal calfserum (a balanced salt solution) at 2 ml/gram of tumor. Then 0.1 ml ofthis tumor suspension is implanted into the flank of the mouse. Ten daysto two weeks after implantation (when the tumors could be measured witha caliper), unless otherwise indicated, the drug therapy was initiated.

In general, drugs are delivered according to the following schedule.Every day the mice are weighed to deter the amount to be injected and asan index of toxicity.

The Tumor Volume is calculated from the measurements by the formula:length (mm)×width (mm)×width (mm)×π/6 as a % of Day 1.

Experiment 1

This experiment was designed to determine the effect of 3TC, FTC orLFD4C alone and in combination with 5-Fluorouracil with leucovorinrescue on the growth of mouse tumor (colon 38) in immuno-competent mice.The drugs were administered to the mice according to the followingschedule:

Control—vehicle only;

5FU/LV—150 mg/kg each i.p. once on day one

3TC—100 mg/kg p.o. b.i.d. for 5 days

FTC—100 mg/kg p.o. bid for 5 days

LFD4C—20 mg/kg p.o. b.i.d. for 5 days

Combination groups received both treatments as per above schedules.

FIG. 1 indicates that 3TC, FTC and LFD4C slows down the growth of colon38 mouse tumor in immunocompetent mice. The effect lasted well past the5 day therapy. In each instance the effect of each of these nucleosideanalogs on the anti-cancer activity of 5-FU/LV was significant (additiveor synergistic).

In FIG. 1, the following legend applies:

Control—vehicle only;

5—FU/LV (150 mg/kg each) ip once on day one;

3TC (100 mg/kg) p.o.b.i.d.×5 days;

FTC (100 mg/kg) p.o.b.i.d.×5 days;

LFd4C (20 mg/kg) p.o.b.i.d.×5 days;

Combination groups received both treatments as per above. Experiment 2

Experiment 2 tested the effects of 3TC, FTC and LFD4C (same schedule asabove) on the enhancement of anti-cancer drug effect of oxaliplatin (10mg/kg i.p., once on day 1) on colon 38 growth in C57BL6 female mice.FIG. 2 shows the results of the experiment, where each of 3TC, FTC andLFD4C clearly enhanced the anti-tumor effect of oxaliplatin on colon 38(additive or synergistic). The effect lasts well after the treatment isstopped.

In FIG. 2, the following legend applies:

Control—vehicle only;

3TC and FTC (100 mg/kg) p.o.b.i.d. day 1-5;

LFd4C (15 mg/kg) p.o.b.i.d. days 1-5;

Oxaplatin (10 mg/kg) i.p. once on day 1;

Combination groups received both treatments as described above.

1. A pharmaceutical composition comprising an effective amount of atleast one compound according to the structure:

Where S is

X is H or F; R¹ is H, an acyl group, a C₁₋₂₀ alkyl or ether group, aphosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as ananticancer or antiviral compound such that an amino group or hydroxylgroup from said biologically active agent forms a phosphate,phosphoramidate, carbonate or urethane group with the adjacent moiety;Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferablyH or a C₁-C₁₂ alkyl group; k is 0-12, preferably, 0-2; R² is H, an acylgroup or a C₁-C₂₀ alkyl or ether group; and pharmaceutically acceptablesalts, solvates or polymorphs thereof, optionally in combination with aneffective amount of an additional anti-cancer agent, and optionally, apharmaceutically acceptable carrier, additive or excipient.
 2. Thecomposition according to claim 1 wherein said anti-cancer compound is anantimetabolite, an inhibitor of topoisomerase I and II, an alkylatingagent or a microtubule inhibitor.
 3. The composition according to claim1 wherein said anti-cancer compound is selected from the groupconsisting of Aldesleukin; Alemtuzumab; alitretinoin; allopurinol;altretamine; amifostine; anastrozole; arsenic trioxide; Asparaginase;BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfanintravenous; busulfan oral; calusterone; capecitabine; carboplatin;carmustine; carmustine with Polifeprosan 20 Implant; celecoxib;chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine;cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D;Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin;Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicinliposomal; Dromostanolone propionate; Elliott's B Solution; epirubicin;Epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16);exemestane; Filgrastim; floxuridine (intraarterial); fludarabine;fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelinacetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide;imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan;letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine(nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine(6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane;mitoxantrone; nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin;oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase;Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin;porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab;Sargramostim; streptozocin; talbuvidine (LDT); talc; tamoxifen;temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG);thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin(ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC);vinblastine; vinorelbine; zoledronate; and mixtures thereof.
 4. Thecomposition according to claim 1 wherein R¹ is H, a C₂-C₁₈ acyl group ora phosphate group and R² is H.
 5. The composition according to claim 1wherein R¹ is H and R² is H.
 6. A method of treating a tumor or cancerin a patient in need thereof comprising administering to said patient aneffective amount of a compound according to the structure:

Where S is

X is H or F; R¹ is H, an acyl group, a C₁₋₂₀ alkyl or ether group, aphosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as ananticancer or antiviral compound such that an amino group or hydroxylgroup from said biologically active agent forms a phosphate,phosphoramidate, carbonate or urethane group with the adjacent moiety;Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferablyH or a C₁-C₁₂ alkyl group; k is 0-12, preferably, 0-2; R² is H, an acylgroup or a C₁-C₂₀ alkyl or ether group; and pharmaceutically acceptablesalts, solvates or polymorphs thereof., optionally in combination withan effective amount of at least one additional anti-cancer agent.
 7. Themethod according to claim 6 wherein said tumor is benign.
 8. The methodaccording to claim 7 wherein said tumor is cancerous.
 9. The methodaccording to any of claim 6 wherein said cancer is selected from thegroup consisting of stomach, colon, rectal, liver, pancreatic, lung,breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder,renal, brain/CNS, head and neck, throat, Hodgkin's disease,non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, acutelymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, smallcell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor,neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx,kidney cancer and lymphoma cancer.
 10. The method according to claim 6wherein said cancer is leukemia.
 11. The method according to claim 6wherein said cancer is colon cancer.
 12. The method according to claim 6wherein said cancer is bladder.
 13. The method according to claim 6wherein said cancer is prostate.
 14. The method according to claim 6wherein said cancer is breast.
 15. The method according to claim 6wherein said cancer is lung cancer.
 16. The method according to claim 6wherein said cancer is nasopharyngeal cancer.
 17. The method accordingto claim 6 wherein said cancer is ovarian cancer.
 18. The methodaccording to claim 6 wherein said cancer is lymphoma.
 19. The methodaccording to claim 6 wherein said cancer is hepatocellular.
 20. Themethod according to claim 6 wherein said cancer is melanoma.
 21. Themethod according to claim 6 wherein said compound is coadministered withan effective amount of at least one additional anti-cancer compound. 22.The method according to claim 21 wherein said anti-cancer compoundanti-cancer compound is an antimetabolite, an inhibitor of topoisomeraseI and II, an alkylating agent or a microtubule inhibitor.
 23. The methodaccording to claim 21 wherein said anti-cancer compound is selected fromthe group consisting of Aldesleukin; Alemtuzumab; alitretinoin;allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide;Asparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin;busulfan intravenous; busulfan oral; calusterone; capecitabine;carboplatin; carmustine; carmustine with Polifeprosan 20 Implant;celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide;cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycinD; Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin;Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicinliposomal; Dromostanolone propionate; Elliott's B Solution; epirubicin;Epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16);exemestane; Filgrastim; floxuridine (intraarterial); fludarabine;fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelinacetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide;imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan;letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine(nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine(6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane;mitoxantrone; nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin;oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase;Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin;porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab;Sargramostim; streptozocin; talbuvidine (LDT); talc; tamoxifen;temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG);thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin(ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC);vinblastine; vinorelbine; zoledronate; and mixtures thereof.
 24. Themethod to claim 6 wherein R¹ is H, a C₂-C₁₈ acyl group or a phosphategroup and R² is H.
 25. The method according to claim 6 wherein saidcompound is 3TC, FTC, LFD4C or mixtures thereof.
 26. A method oftreating psoriasis, genital warts or a hyperproliferative disease in apatient in need thereof comprising administering to said patient aneffective amount of a compound according to the structure:

Where S is

X is H or F; R¹ is H, an acyl group, a C₁-C₂₀ alkyl or ether group, aphosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such that anamino group or hydroxyl group from said biologically active agent formsa phosphate, phosphoramidate, carbonate or urethane group with theadjacent moiety; Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ethergroup, preferably H or a C₁-C₁₂ alkyl group; k is 0-12, preferably, 0-2;R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group; andpharmaceutically acceptable salts, solvates or polymorphs thereof.
 27. Amethod according to claim 26 wherein R¹ is H, a C₂-C₁₈ acyl group or aphosphate group and R² is H.
 28. The method according to claim 26wherein said compound is 3TC, FTC, LFD4C or mixtures thereof.
 29. Themethod according to claim 26 wherein said hyperproliferative disease ishyperkeratosis, ichthyosis, keratoderma or lichen planus.
 30. A methodof treating HCV or a chronic inflammatory disease comprisingadministering to a patient in need of treatment an effective amount of acompound according to the structure:

Where S is

X is H or F; R¹ is H, an acyl group, a C₁₋₂₀ alkyl or ether group, aphosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as ananticancer or antiviral compound such that an amino group or hydroxylgroup from said biologically active agent forms a phosphate,phosphoramidate, carbonate or urethane group with the adjacent moiety;Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferablyH or a C₁-C₁₂ alkyl group; k is 0-12, preferably, 0-2; R² is H, an acylgroup or a C₁-C₂₀ alkyl or ether group; and pharmaceutically acceptablesalts, solvates or polymorphs thereof.
 31. The method according to claim30 wherein said chronic inflammatory disease is rheumatoid arthritis orosteoarthritis.
 32. A compound according to the structure:

Where S is

X is H or F; R¹ is a

Where Nu is a radical of a biologically active compound such that anamino group or hydroxyl group from said biologically active agent formsa phosphate, phosphoramidate, carbonate or urethane group with theadjacent moiety; each R⁸ is independently H, or a C₁-C₂₀ alkyl or ethergroup, preferably a C₁-C₁₂ alkyl group; k is 0-12, preferably, 0-2; R²is H, an acyl group or a C₁-C₂₀ alkyl or ether group; andpharmaceutically acceptable salts, solvates or polymorphs thereof. 33.The compound according to claim 32 wherein Nu is a radical of ananticancer agent selected from the group consisting of Aldesleukin;Alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine;anastrozole; arsenic trioxide; Asparaginase; BCG Live; bexarotenecapsules; bexarotene gel; bleomycin; busulfan intravenous; busulfanoral; calusterone; capecitabine; carboplatin; carmustine; carmustinewith Polifeprosan 20 Implant; celecoxib; chlorambucil; cisplatin;cladribine; cyclophosphamide; cytarabine; cytarabine liposomal;dacarbazine; dactinomycin; actinomycin D; Darbepoetin alfa; daunorubicinliposomal; daunorubicin, daunomycin; Denileukin diftitox, dexrazoxane;docetaxel; doxorubicin; doxorubicin liposomal; Dromostanolonepropionate; Elliott's B Solution; epirubicin; Epoetin alfa estramustine;etoposide phosphate; etoposide (VP-16); exemestane; Filgrastim;floxuridine (intraarterial); fludarabine; fluorouracil (5-FU);fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea;Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate;Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole;leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogenmustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP);mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone;nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin;paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim;pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium;procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim;streptozocin; talbuvidine (LDT); talc; tamoxifen; temozolomide;teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa;topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA);Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine;vinorelbine; zoledronate; and mixtures thereof.
 34. The compoundaccording to claim 32 wherein Nu is a radical of an anti-viral agent.35. The method according to claim 26 wherein said compound isco-administered with an anti-hyperproliferative agent. 36-55. (canceled)